Drug Resistance and Cardiovascular Safety of Second-Generation Anti-Androgens in Patients with Advanced Prostate Cancer : Second-Generation Antiandrogen Use in Advanced Prostate Cancer.

Prostate cancer is recognized as one of the most common cancers affecting the male population. The prostate is revealed to be a hormone-dependent tissue as testosterone and dihydrotestosterone could bind to the androgen receptor, activate it, and initiate the nuclear translocation of this receptor, followed by subsequent signaling cascades. Regarding this androgen dependency on the prostate, it is believed that androgen deprivation therapies can confront aggressive prostate cancer as a first-line treatment. However, prostate cancer could overcome hormone deprivation strategies through several cellular mechanisms, such as intratumoral androgen production and the production of ligand-independent androgen receptor splice variants, known clinically as castration-resistant prostate cancer. Due to the limited efficacy of first-generation anti-androgens in complete blockage of androgen receptor activity, recently, four second-generation anti-androgens, including abiraterone acetate, enzalutamide, apalutamide, and darolutamide approved by the United States Food and Drug Administration, and considered standard of care for patients with advanced prostate cancer. In addition to some reports of drug resistance treatments, cardiotoxicity, including heart failure, ventricular repolarization, hypertension, myocarditis, atrial fibrillation, and ischemic heart diseases, is commonly observed in patients who underwent abiraterone acetate and/or enzalutamide therapy. However, cardiotoxicity has rarely been observed after treatments of apalutamide and/or darolutamide.